Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome
Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome
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DOI：
10.1073/pnas.0404587101
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发表时间：
2004-10-26
影响因子：
11.1
通讯作者：
Tanaka, K
中科院分区：
文献类型：
--
作者：
Horibata, K;Iwamoto, Y;Tanaka, K
紫外线敏感综合征(UVS)-S-S是一种罕见的常染色体隐性遗传病，以光敏和轻度雀斑为特征，但没有神经系统异常或皮肤肿瘤。(紫外线)-S-S细胞表现出流行性乙型脑炎病毒超敏反应和转录偶联缺陷的DNA修复的紫外线损伤。提示(UVS)-S-S不属于已知的光敏性疾病如着色性干皮病和Cockayne综合征(CS)的任何互补组。为了确定与紫外光敏感相关的S-S基因，我们进行了基于紫外光敏感功能互补的微细胞介导的染色体转移。我们发现其中一株紫外线-S-S细胞系UV(S)1KO在人类10号染色体被转移后获得了紫外线抗性。由于CS B组(CSB)的致病基因位于第10号染色体上，它涉及神经系统异常和光敏反应，以及紫外线损伤的转录偶联修复缺陷，因此我们对UV(S)1KO中的CS B基因进行了测序，并检测到一个纯合子零突变。我们的结果表明，以前对UV(S)1KO的互补分析是错误的。这一发现令人惊讶，因为CSB基因的零突变预计会导致CS特征，如严重的发育和神经异常。另一方面，从无血缘关系的患者中获得的(UVS)-S-S细胞系KPS3中未检测到CSB基因突变和CSB蛋白的正常表达，表明(UVS)-S-S细胞系具有遗传异质性。本文对UV(S)1KO的基因型-表型关系的差异提出了可能的解释。
UV-sensitive syndrome ((UVS)-S-s) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors. (UVS)-S-s cells show IJV hypersensitivity and defective transcription-coupled DNA repair of UV damage. It was suggested that (UVS)-S-s does not belong to any complementation groups of known photosensitive disorders such as xeroderma pigmentosum and Cockayne syndrome (CS). To identify the gene responsible for (UVS)-S-s, we performed a microcell-mediated chromosome transfer based on the functional complementation of UV hypersensitivity. We found that one of the (UVS)-S-s cell lines, UV(s)1KO, acquired UV resistance when human chromosome 10 was transferred. Because the gene responsible for CS group B (CSB), which involves neurological abnormalities and photosensitivity as well as a defect in transcription-coupled DNA repair of UV damage, is located on chromosome 10, we sequenced the CSB gene from UV(s)1KO and detected a homozygous null mutation. Our results indicate that previous complementation analysis of UV(s)1KO was erroneous. This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities. On the other hand, no mutation in the CSB cDNA and a normal amount of CSB protein was detected in Kps3, a (UVS)-S-s cell line obtained from an unrelated patient, indicating genetic heterogeneity in (UVS)-S-s. Possible explanations for the discrepancy in the genotype-phenotype relationship in UV(s)1KO are presented.